Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease

Blood. 2009 Oct 1;114(14):3101-12. doi: 10.1182/blood-2009-05-219402. Epub 2009 Jul 14.


In acute graft-versus-host disease (GVHD), naive donor CD4(+) T cells recognize alloantigens on host antigen-presenting cells and differentiate into T helper (Th) subsets (Th1, Th2, and Th17 cells), but the role of Th subsets in GVHD pathogenesis is incompletely characterized. Here we report that, in an MHC-mismatched model of C57BL/6 donor to BALB/c recipient, WT donor CD4(+) T cells predominantly differentiated into Th1 cells and preferentially mediated GVHD tissue damage in gut and liver. However, absence of interferon-gamma (IFN-gamma) in CD4(+) T cells resulted in augmented Th2 and Th17 differentiation and exacerbated tissue damage in lung and skin; absence of both IL-4 and IFN-gamma resulted in augmented Th17 differentiation and preferential, although not exclusive, tissue damage in skin; and absence of both IFN-gamma and IL-17 led to further augmentation of Th2 differentiation and idiopathic pneumonia. The tissue-specific GVHD mediated by Th1, Th2, and Th17 cells was in part associated with their tissue-specific migration mediated by differential expression of chemokine receptors. Furthermore, lack of tissue expression of the IFN-gamma-inducible B7-H1 played a critical role in augmenting the Th2-mediated idiopathic pneumonia. These results indicate donor CD4(+) T cells can reciprocally differentiate into Th1, Th2, and Th17 cells that mediate organ-specific GVHD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • B7-1 Antigen / physiology
  • B7-H1 Antigen
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / pathology
  • Cell Differentiation*
  • Cell Movement
  • Flow Cytometry
  • Graft vs Host Disease / immunology*
  • Graft vs Host Disease / metabolism
  • Graft vs Host Disease / pathology*
  • Idiopathic Interstitial Pneumonias / etiology
  • Idiopathic Interstitial Pneumonias / pathology
  • Interferon-gamma / physiology
  • Interleukin-17 / physiology
  • Interleukin-4
  • Lung / immunology
  • Lung / pathology
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutralization Tests
  • Peptides / physiology
  • Skin / immunology
  • Skin / pathology
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Helper-Inducer / pathology*
  • Th1 Cells / immunology
  • Th1 Cells / pathology*
  • Th2 Cells / immunology
  • Th2 Cells / pathology*


  • Antibodies, Monoclonal
  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Interleukin-17
  • Membrane Glycoproteins
  • Peptides
  • Interleukin-4
  • Interferon-gamma